Clonal hematopoiesis, epigenetic changes, social determinants of health, and behavioral risk factors as predictors of accelerated aging in HIV - SUMMARY Effective antiretroviral therapy (ART) has dramatically reduced mortality, therefore people with HIV (PWH) are now surviving into middle and old age. Despite this success, PWH experience high rates of multimorbidities, and functional and cognitive decline at a younger age than those without HIV, a phenomenon known as accelerated aging. Thus, there is an urgent need to focus not just on mortality but on healthspan, or the time someone is healthy not just alive, by defining the drivers of the accelerated aging. Epigenetic clocks are powerful tools for predicting aging-associated diseases and lifespan in the general population; however, there are little data on the effects of HIV and ART on epigenetic aging in older PWH. More recently, clonal hematopoiesis, a noncancerous expansion of a somatic blood cell clone, of indeterminate potential (CHIP) has been shown to be associated with increased risk for hematological cancers, cardiovascular (CVD) and pulmonary diseases, obesity, osteoporosis, and all-cause mortality, in the general population. Importantly, the prevalence of CHIP is much higher and onset earlier among PWH. Moreover, CHIP has been more commonly identified in PWH with CVD, sometimes years before CVD diagnosis. However, data are lacking on its contribution to other age-related outcomes in PWH. Moreover, the modifying effects of underlying genetic predisposition, socio-behavioral aspects and other HIV- specific risk factors are largely unknown limiting our ability to prevent or slow down functional and cognitive decline and multimorbidity. CFAR Network of Integrated Clinical Systems (CNICS) is a large, well-characterized, prospective gender, and racially/ethnically diverse cohort with ~49,000 PWH. CNICS captures rich longitudinal clinical data, patient-reported measures and outcomes, health-related quality of life (HRQL), and additional social determinants of health factors, and provides access to a biospecimen repository. We will leverage and build on the extensive platform and data collection of CNICS to identify the drivers of accelerated aging. We hypothesize that the interplay of epigenetic changes and CHIP with genetic predisposition and HIV-specific and socio- behavioral factors drive functional and cognitive decline, multimorbidity, and mortality among PWH. In Aim 1, we will establish a sub-cohort from 6,442 already enrolled PWH ages ≥50 years with existing biospecimens and prospective clinical data and determine the role of the epigenetic aging, genetic predisposition, and socio- behavioral factors in functional and cognitive decline, osteoporosis, multimorbidity, HRQL, and morbidity in PWH. In Aim 2, we will generate whole exome sequencing data to identify specific CHIP-driving mutational patterns that define different risk of developing adverse age-related outcomes and explore the interplay between CHIP and epigenetic changes in PWH. In Aim 3, we will use Mendelian randomization to detect the causal effect of epigenetic aging and CHIP on age-related diseases and identify potential drugs that may reverse adverse outcomes. Understanding the predisposition to and the impact of accelerated aging is critical to identifying PWH at high risk, developing preventive and therapeutic strategies, and improving the healthspan in the setting of HIV.
